TY - JOUR
T1 - Oxidative Stress-Induced Damage to the Developing Hippocampus Is Mediated by GSK3b
AU - Abbah, Joseph
AU - Vacher, Claire Marie
AU - Goldstein, Evan Z.
AU - Li, Zhen
AU - Kundu, Srikanya
AU - Talbot, Brooke
AU - Bhattacharya, Surajit
AU - Hashimoto-Torii, Kazue
AU - Wang, Li
AU - Banerjee, Payal
AU - Scafidi, Joseph
AU - Smith, Nathan A.
AU - Chew, Li Jin
AU - Gallo, Vittorio
N1 - Publisher Copyright:
Copyright © 2022 Abbah et al.
PY - 2022/6/15
Y1 - 2022/6/15
N2 - Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 b activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 b during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.
AB - Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 b activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 b during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.
KW - Akt
KW - GABA
KW - POMC
KW - excitation–inhibition balance
KW - interneurons
KW - memory
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U2 - 10.1523/JNEUROSCI.2389-21.2022
DO - 10.1523/JNEUROSCI.2389-21.2022
M3 - Article
C2 - 35589394
AN - SCOPUS:85132452953
SN - 0270-6474
VL - 42
SP - 4812
EP - 4827
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 24
ER -